Studies have shown that the terminals of specialized neurons of the brain contain presynaptic nicotinic receptors which, when stimulated, cause the release of neurotransmitters. The nicotine-induced release of dopamine from terminals of the mesolimbic and nigrostriatal systems is thought to produce the positively reinforcing properties of nicotine responsible for cigarette smoking. Although considerable research has been conducted on the molecular structure, localization and ligand binding properties of central nicotinic receptors; their functional properties have not been well characterized. Our recent studies have shown that prior nicotine treatment results in a desensitization of nicotine-stimulated dopamine release from striatal synaptosomes. Using the technique of in vitro superfusion, we plan to extend our studies to investigate the effects of intermittent schedules of treatment, temperature dependence and regional differences in nicotine-inducted desensitization of neurotransmitter release. In addition, the effect of the active nicotine metabolite, nornicotine, will be investigated, as will the apparent ability of low concentrations of nicotine to enhance basal neurotransmitter release with prolonged exposure. The ability of nicotine to desensitize receptor in vivo has been suggested as the mechanism by which chronic administration of the drug results in the development of nicotine tolerance and increased nicotinic receptor density. In particular, the concentration of nicotine, brain area affected, and time-course of treatment appear to be important determinants of the drug's effect. In this project we plan to investigate the ability of various nicotine administration protocol to upregulate nicotinic receptors in rat striatum and cerebral cortex. This will be coupled with measurements of plasma and brain levels of nicotine and nornicotine during administration. The overall objective of these studies is to characterize the effects of prior nicotine exposure with respect to desensitization and long-term regulation of central nicotinic receptors. This characterization will increase our understanding of how nicotine influences central neurotransmission and how the responses which it produces are affected by the time course, schedule and duration of its delivery. The processes of receptor desensitization and upregulation could have important implications on cigarette smoking where nicotine is taken at intermittent schedules for long periods of time. A better understanding of the dynamics of nicotine's effects on neurotransmitter systems in the brain is crucial in our attempts to develop successful smoking cessation programs as well as our ability to understand the central reinforcing pathways upon which nicotinic drugs exert their effects.